A new study from P&S and Stanford University suggests that brain cells called astrocytes may be behind the accumulation of beta-amyloid peptide in the brain that causes Alzheimer's disease.

Alzheimer's, most researchers believe, is caused when a small peptide, beta-amyloid, accumulates in the brain. The peptide is made throughout life, but in people with Alzheimer's, either too much is made or too little is degradedor bothand the excess peptide forms aggregates that accumulate throughout the brain. The aggregated beta-amyloid has been implicated in neuron death, which eventually leads to dementia.

Researchers have known that cells called microglia, which surround beta-amyloid deposits in the AD brain, can ingest and destroy the beta-amyloid peptide in cell culture, so they've been trying to stimulate the cells to do the same in vivo. But the role of astrocytes, which are also present at sites of beta-amyloid deposition, hadn't been examined.

The new findings show that normal adult astrocytes also can degrade beta-amyloid, suggesting that treatments to boost astrocyte activity in Alzheimer's may be beneficial. "This is the first study to show that adult astrocytes can degrade beta-amyloid," says Dr. Jens Husemann, the study's senior author and associate research scientist in the Department of Physiology and Cellular Biophysics. "In addition, astrocytes outnumber microglia in the brain, so they may be very important. Now labs will explore ways to activate astrocytes to increase beta-amyloid removal." The research was published March 3 on the Nature Medicine Web site and will appear in the April print issue.

Adult astrocytes in the left figure (nuclei are stained blue) ingest and concentrate beta-amyloid around the nuclei. Within 24 hours, the cells, seen in the center photo, degrade the ingested proteins. The photo on the right shows beta-amyloid on a slide before astrocyte cells were added.

The research group, including Dr. Samuel Silverstein, the John C. Dalton Professor of Physiology and Cellular Biophysics; Dr. John Loike, research scientist; and Dr. Tony Wyss-Coray from Stanford, also speculates that Alzheimer's may be caused by astrocyte dysfunction. It is still unknown why beta-amyloid accumulates in people with the late onset form of the disease, but one possibility is that the astrocytes fail to degrade the peptide. Dr. Husemann and his colleagues are now looking at astrocytes from the brains of Alzheimer's patients and mice with a similar Alzheimer's-like disease to see if their cells are still capable of destroying beta-amyloid.

In the Nature Medicine study, the researchers found that when they placed cultured adult mouse astrocytes onto brain tissue taken from Alzheimer's model mice, the astrocytes ingested beta-amyloid. The astrocytes reduced the amount of beta-amyloid in the brain tissue by 40 percent within 24 hours.

To see if the astrocytes also degradedas well as ingestedbeta-amyloid, they incubated adult mouse astrocytes in media containing this peptide. At the beginning of the incubation, all beta-amyloid was in the media. In the next 24 hours, the researchers saw that all of the beta-amyloid moved into the astrocytes and then disappeared completely, indicating that the astrocytes had degraded the beta-amyloid and had not exported it.

Though it has been known that astrocytes can eat and destroy proteins in general, no one has published work showing that the cells could consume beta-amyloid specifically. Dr. Husemann says they only discovered the astrocyte's ability when they looked at adult cells instead of the more commonly studied neonatal cells. Only the adult cells from mice destroyed the beta-amyloid; the neonatal cells did not.

The difference between adult and neonatal cells raises a question about which is the right Alzheimer's research model. Neonatal cells are used more often since they are much easier to culture than adult cells, but Dr. Husemann says "we need to do more experiments to identify the differences between adult and neonatal astrocytes."

Though the researchers suggest improving the astrocytes' ability to degrade beta-amyloid may be therapeutic, they caution that other astrocyte functions may contribute to the disease. "Studies suggest that upon interaction with beta-amyloid astrocytes may release inflammatory molecules that damage neurons," Dr. Husemann says.

Last year, brain inflammation in patients halted the clinical trials conducted by a pharmaceutical company of an Alzheimer's vaccine. In mice, the vaccine was thought to reduce plaques and relieve disease symptoms by stimulating microglia to devour beta-amyloid deposits in the brain. "It will be a delicate balancing act to stimulate beta-amyloid removal while keeping inflammation down at the same time," Dr. Husemann says.

The research was supported by the Alzheimer's Disease Research Center at P&S, the NIH, and the Alzheimer's Association.